The approval was based on findings from a phase 2b clinical trial that was conducted under the FDA's special protocol assessment. In the trial, the radiopharmaceutical elicited a 50 percent or higher reduction in antihypertensive medication use for at least six months, which was the primary endpoint of the trial, for 25 percent of patients with PPGL. In those receiving at least two therapeutic doses, the primary endpoint was achieved for 32 percent of patients.

Prior to submission of the NDA, Azedra was granted a breakthrough therapy designation for the treatment of PPGL, along with orphan drug and fast track designations.

The novel version of Azedra is made using a system known as UltraTrace, which results in less non-radioactive MIBG during enrichment leading to greater delivery of radiation to the tumor. The UltraTrace technology was developed by Molecular Insight Pharmaceuticals, which was acquired by Progenics in early 2013.

The pivotal, open-label clinical trial enrolled 68 patients with MIBG-avid PPGL who were ineligible for curative surgery, failed prior therapy, or were not candidates for chemotherapy. Azedra was given at an initial dosimetric dose of 111 to 222 MBq at the time of enrollment, which was followed by a therapeutic dose of 296 MBq/kg. Three months after the first dose, a second therapeutic dose of 18.5 GBq was administered. In total, 50 patients received both therapeutic doses per protocol.

The primary endpoint of reduction in antihypertensive medication was selected since PPGL leads to higher levels of catecholamines and subsequently hypertension and other cardiovascular issues. All patients in the trial were receiving antihypertensive therapy for at least 30 days prior to entry in the study. The key secondary endpoint of the study focused on the objective response rate (ORR) by RECIST criteria.

Prior to enrollment, 71 percent of patients had received two or more prior lines of therapy. Most patients had a diagnosis of pheochromocytoma (71.6 percent), with the remainder having paraganglioma (28.4 percent). Prior treatment included surgery for 89.2 percent of patients. Additionally, 29.7 percent of those enrolled in the trial had received traditional I-131 MIBG therapy and 37.6 percent of patients had received chemotherapy.

The ORR, which consisted entirely of partial responses, was 23.4 percent with Azedra for all patients enrolled in the trial. Additionally, stable disease (SD) was achieved for 68.8 percent of patients, for a disease control rate (ORR + SD) of 92.2 percent. In the per protocol group, the ORR was 30 percent and 68 percent of patients had stable disease. The disease control rate was 98 percent.

In addition to those meeting the primary endpoint, 31.4 percent of patients had a 50 percent or more reduction in antihypertensive medication use; however, this did not last longer than six months. For those achieving the primary endpoint, the median duration of clinical benefit was 13.3 months (range, 8.0-60.2).

The median time from enrollment to death was 36.7 months. Survival did not differ based on the site of metastatic disease. Those with lung metastases had a median survival of 42.6 months and those with liver metastases had a median survival of 41.1 months.

There were no unexpected adverse events (AEs) in the trial. The most common treatment-emergent AEs, which occurred in more than 50 percent of patients, included nausea, myelosuppression and fatigue. There were no acute drug-related hypertensive crises reported in the trial nor were there any new cases of severe acute hypertension.

An expanded access program for Azedra is currently available for patients with MIBG-avid malignant and/or recurrent PPGL. Outside of providing access to the medication, the program also plans to further assess safety (NCT02961491).